| Autor: |
Kugaevskaya EV; Institute of Biomedical Chemistry, Moscow, Russia., Veselovsky AV; Institute of Biomedical Chemistry, Moscow, Russia., Indeykina MI; Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.; Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.; Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia., Solovyeva NI; Institute of Biomedical Chemistry, Moscow, Russia., Zharkova MS; Institute of Biomedical Chemistry, Moscow, Russia., Popov IA; Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.; Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.; Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia., Nikolaev EN; Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Moscow, Russia.; Moscow Institute of Physics and Technology, Dolgoprudnyi, Moscow Region, Russia.; Skolkovo Institute of Science and technology, Moscow, Russia., Mantsyzov AB; Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia., Makarov AA; Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia., Kozin SA; Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia. kozinsa@gmail.com. |
| Abstrakt: |
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-β (Aβ) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same Aβ sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and Aβ of these rodents (ratAβ) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves Aβ-derived peptide substrates, however, there are contradictions concerning the localization of the cleavage sites within Aβ and the roles of each of the two ACE catalytically active domains in the hydrolysis. In the current study by using mass spectrometry and molecular modelling we have tested a set of peptides corresponding to MBDs of Aβ and ratAβ to get insights on the interactions between ACE and these Aβ species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the Aβ and ratAβ MBDs with C-amidated termini, thus assuming that full-length Aβ and ratAβ can be hydrolyzed by N-ACE in the same endopeptidase mode. Taken together with the recent data on the molecular mechanism of zinc-dependent oligomerization of Aβ, our results suggest a modulating role of N-ACE in AD pathogenesis. |
